The efficacy of angiotensin converting enzyme (ACE) inhibitors in the treatment of hypertension and congestive heart failure is known and has been amply demonstrated [U.S. Pat. No. 4,374,829, A. A. Patchett, et al., Nature, 288, 280-283 (1980); D. M. Gross, et al., J. Pharm. and Expt. Ther., 216, 552-557 (1981)]. The use of such ACE inhibitors indicates the positive effects of control of Angiotensin II (A II) levels in a variety of renal disease states [C. D. Smith, et al., Arthritis and Rheumatism (1984)].
It has been generally known for some time that a renal factor is involved in some forms of hypertension, but only relatively recently have some of the complete relationships in the "renin angiotensin system" been elucidated. In addition to its direct vasopressor effects and its control of adrenal secretion of aldosterone, A II has a direct effect on glomerular size and basement membrane porosity. [D. P. Haley, et al., Abstract of Proceedings of Amer. Soc. of Nepth; 151A (1983); S. J. Hoorntje.]
Heretofore, clinical studies have been directed to the blockade of the renin angiotensin system in the systemic circulation to control hypertension and congestive heart failure. Specific renin angiotensin systems have been observed to be present within the cells of specific organ systems such as, for example, the kidney, heart, brain, and blood vessels. M. R. Celio, et al. [Proc. Natl. Acad. Sci. USA, 78, 3897 (1981) and Histochemistry, 72, 1 (1981)] have identified in rats the specific glomerular sites of A II production from angiotensin I (A I) and have demonstrated its subsequent blockage by the ACE inhibitor compound, enalapril.
It has also been found that infusions of A II onto preparations of renal glomeruli produced shrinking of the glomerulus and smudging of the foot processes which is attendant with the development of proteinuria. [S. J. Hoorntje, supra]. Upon elimination of the infused A II, these actute, transitory changes disappear and proteinuria, glomerular volume, and foot processes configurations then return to normal. Although it has not yet been established, it appears that glomerular sclerosis plays a major role in progressive degradation of renal function regardless of the original etiology of the kidney disease. Clinically, it has been postulated that control of proteinuria in renal disease would result in controlling the underlying renal pathology. [R. B. Miller, et al., Amer. J. Med., 46, 919 (1969)].
It has also been known that hypertension can produce renal disease and that renal disease can produce hypertension [Renal and Electrolyte Disorders, 282, Ed by R. W. Schrier (1976)]. Although the control of hypertension through the use of ACE inhibitors has been established [M. Burnier, et al., Amer. J. of Physiology, 245, 203 (1983); H. R. Brunner, et al., Am. Int. Med., 90, 19 (1979)] it has yet to be determined that subsequent development of renal diseases will be ablated or even blunted by these agents.
Diabetic nephropathy is also known to be associated with specific lesions in the kidney and eye, hypertension [D. Myers, et al, Clin. Res., 27:316A, (1979)], and relative increases in circulating renin [W. A. Hsueh, et al, J. Clin. Endo. Metab., 51:535, (1980)]. It has been postulated that the vascular lesions are related to the vasculotoxic effects of A II. Therefore, the inhibition of A II would be expected to have a positive effect on the course of the renal disease.
It has been demonstrated that administration of the ACE inhibitor, enalapril, effectively blocks the pressor response to exogenous administered A I and significantly suppresses the activity of circulating converting enzyme for periods of up to about 24 hours. [D. M. Gross, et al., J. Pharm. and Expt. Ther., 216, 552-557 (1981)]. Specific localization of enalapril in the kidney has been demonstrated as has its specific effect on the local production of A II within the glomerulus. As reported by D. E. Hricik, et al. [N. E. J. Med., 308, 373 (1983)], one might assume that in the A II dependent arterial stenotic kidney, renal insufficiency could occur upon administration of enalapril. However, it has been demonstrated that administration of enalapril in renin dependent states, such as renal vascular hypertension, results in virtual total control of blood pressure [S. Franklin, Am. J. Med., 79, 14 (1985)].
As reported by S. Anderson et al., [J. Clin. Investigation, in press (1986)], protection against the progression of renal disease in hypertensive rats was accomplished with the addition of enalapril, but not with the addition of standard antihypertensive medication (reserpine, hydralazine, and hydrochlorothiazide). Although both therapies controlled blood pressure compared to control animals, intraglomerular pressure (.DELTA.P), basement membrane characteristics (K.sub.f), and resulting proteinuria and glomerulosclerosis were controlled with ACE inhibition therapy, but not with the standard triple therapy. The degree of proteinuria and glomerulosclerosis in the standard triple therapy was similar to untreated animals. Thus, it is demonstrated that control of systemic blood pressure alone does not positively effect the progression of renal disease.